What’s New in Pre-Aging Topical Modalities: The Clinical Efficacy of Acetyl Dipeptide-31 Amide

Santina Conte MD¹, Monica K. Li MD FRCPC FAAD²

¹Division of Dermatology, McGill University, Montreal, Quebec, Canada
²Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada

Conflicts of Interest: Monica K. Li is a consultant and speaker for Kenvue, L’Oreal, Galderma, Beiersdorf and Pierre Fabre.

Abstract

Skin aging, caused by a combination of intrinsic and extrinsic factors, leads to decreased collagen, elastin and hydration levels with subsequent volume loss, dullness, uneven skin tone and fine lines, among other undesirable features. Individuals, especially youth, have become increasingly interested in slowing or preventing the aging process, given the impact of skin appearance on one’s self-esteem, social interactions and overall quality of life. Acetyl dipeptide-31 amide, a novel, multifunctional micropeptide with anti-inflammatory and anti-inflammaging effects, in addition to increased critical extracellular matrix support and positive impacts on cellular pathways and genes involved in skin health, has recently shown promising efficacy in protecting and preserving youthful skin. The purpose of this paper is to review currently available anti-aging treatment modalities and to present acetyl dipeptide-31 amide as a novel, evidence-based, and both preventative and corrective topical option.

Key words: pre-aging, acetyl dipeptide-31 amide, cosmetic peptide, intrinsic skin aging, extrinsic skin aging

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Introduction

Pre-aging, a novel term used to describe self-perceived signs of skin aging that occur in an individual’s third and fourth decades of life, encompasses changes such as dullness, loss of radiance, uneven skin tone, roughness, loss of firmness, dark eye circles, and fine lines.¹ In recent years, social media influences and increasing focus on self-care have driven growing interests amongst young adults in preventing aging. Individuals have become increasingly aware of the skin acting as a mirror of one’s general health status,² with its health and appearance influencing self-esteem, mental status, social interactions and overall quality of life.³ Younger generations are increasingly embracing preventative measures aimed at slowing the aging process, including skincare routines, dietary changes, and regular exercise.² Moreover, differences have been noted in the onset of aging changes, whereby those with less richly pigmented skin are noted to have changes in their mid-twenties, and those with more richly pigmented skin in their mid-thirties, reinforcing the importance of a simple, cost-effective, accessible targeted topical molecule to possibly alter the trajectory of skin aging.

Aging occurs due to extrinsic factors, including environmental factors and outside forces, such as solar radiation, nutrition, air pollution and climate factors;⁴ and intrinsic changes in hormones, genetics, metabolic processes and immune system decline⁵ (Table 1). Subsequent structural deficiencies in the skin affect its physical and functional properties. The primary changes associated with intrinsic aging include thinning, fragility, poor wound healing, xerosis, and compromised barrier function, while fine wrinkles, sagging, and crepiness represent visible cosmetic concerns.^5-7 More precisely, intrinsic skin aging is due to low-level inflammation released by senescent skin cells (termed “inflammaging”), resulting in volume loss in the dermis and below, oxidative stress and damage due to endogenous reactive oxygen species, decreased collagen and elastin production, slower cell turnover, among other reasons.^{5, 8}

Table 1. Extrinsic and intrinsic factors of skin aging

Given the aforementioned understanding of factors underlying intrinsic skin aging, a novel cosmetic anti-inflammatory peptide intended to preserve skin quality and function was formulated. Herein, we explore acetyl dipeptide-31 amide’s mechanism of action and its efficacy in protecting and preserving youthful skin.

Background

Acetyl dipeptide-31 amide (AP31) is a novel, multifunctional micropeptide developed with a focus on eczema and skin aging.⁹ It was specially formulated to be at least two times smaller in size relative to current commercially available counterparts, and similar in size to retinol, with its size well below the 500-Dalton threshold for optimal skin penetration and absorption.⁹ Its capacity to penetrate the stratum corneum was also optimized through modifications of the peptide’s molecular structure.⁹ Such modifications have allowed the molecule to readily penetrate the skin, regardless of the vehicle (cream, lotion, or water-in-silicone base). According to preclinical and clinical studies, AP31 functions in multiple ways, including delivering anti-inflammatory effects and a reduction in inflammaging by significantly reducing inflammatory cytokines interleukin (IL)-4, IL-6, IL-8, IL-17 and tumour necrosis factor (TNF)-⍺. Additionally, AP31 was shown to increase extracellular matrix (ECM) support by increasing critical ECM components, namely procollagen, elastin, decorin, fibronectin and hyaluronic acid, improving firmness, hydration and elasticity.⁹ In vitro studies demonstrated AP31’s favorable influence in cellular pathways related to skin aging and on genes involved in barrier function, skin hydration, skin plumping, and epidermal metabolism.⁹

Clinical Trial #1 findings – Edison et al.⁹

In a prospective, single-arm, single-centre, 16-week study including 38 women aged 40-65 years (mean 54.5 years) with Fitzpatrick skin phototypes I-IV, the clinical efficacy of an AP31-containing formulation was assessed. Inclusion criteria included mild-to-moderate jawline sagging, mild-to-moderate wrinkles, and moderate fine lines. The face cream formulation contained AP31 0.4% with a niosomal carrier and a low concentration of glycolic acid, combined with acetyl tyrosinamide and gluconolactone. Patients were instructed to apply AP31-containing cream on their neck and face twice daily for 16 weeks, with concurrent SPF 35 sunscreen lotion application in the morning. At week 16, the formulation’s clinical efficacy was graded based on 15 parameters: fine lines, wrinkles, pore size, visual roughness, tactile roughness, laxity, jawline sagging, global lift, appearance of nasolabial folds, hyperpigmentation, skin tone evenness, skin clarity, skin radiance/brightness, and overall skin appearance (global face and crow’s feet). Subject self-assessment was also evaluated, including 13 items rated on a 1 to 5 scale (1 = excellent, 5 = poor or none), namely skin tightening, revival, radiance, fullness, firmness, elasticity, hydration, facial and jawline contouring, appearance of fine lines and wrinkles, and whether their skin felt younger looking.⁹

Anti-Aging, Firming, Contouring and Lifting Benefits of AP31

AP31 showed significant improvement in all 15 above-mentioned objective clinical parameters at weeks 12 and 16 (p<0.01), with 7 features significantly improved as early as week 2 (p<0.01). The appearance of nasolabial folds, jawline sagging, and global lift were noted to have the most impressive clinical improvements, with a mean percent improvement of 11%, 9% and 10% at 16 weeks respectively. Other features with notable clinical improvements included fine lines and wrinkles, smoothness and skin tone.

Subjectively, patients noted findings consistent with the above-mentioned expert clinical grading. At week 2, 94% noted firmer, more elastic skin, with 11 of the 13 facial attributes deemed to have improved in over 86% of subjects. The remaining 2 facial features (jawline and facial definition/contouring) were noted to have improved by 76% of subjects, with an increase to 92% by week 16. At the end of the study, 14 of the 16 self-assessed skin attributes were noted to have improved in over 94% of participants, demonstrating clear clinical efficacy of the AP31 formulation.

Toxicity and Tolerability

The product was overall well-tolerated in clinical studies, without adverse events such as edema, erythema, dryness, burning, stinging, itching and tightness. Preclinical studies did not exhibit AP31 concentration-related cytotoxicity.

Clinical Trial #2 findings – Farris et al.¹

A 12-week, single-centre clinical study with 46 women aged 25-55 with Fitzpatrick skin phototypes I-IV was also conducted. Inclusion criteria included mild-to-moderate scores for at least three of six skin parameters, including fine lines, wrinkles, lack of firmness, evenness of skin tone, roughness and lack of radiance. The morning skincare regimen was comprised of a AP31+SPF moisturizer (Neutrogena Collagen Bank SPF Moisturizer^®), while the evening regimen included an AP31+bakuchiol moisturizer (Neutrogena Collagen Bank Moisturizer^®). Specifically, bakuchiol is a monoterpenoid phenol derived from Psoralea corylifolia and felt to have antioxidant, anti-inflammatory, anti-microbial, anti-aging and anti-acne benefits and function similar to retinol.¹ Efficacy parameters included tactile surface roughness, lack of clarity, fine lines, under-eye wrinkles, crow’s feet wrinkles, look of skin firmness/laxity, feel of skin firmness/laxity, lack of skin elasticity, overall unevenness of skin tone, lack of radiance/brightness, blotchiness, photodamage, and elasticity.

Globally, significant improvements in early visible signs of collagen decline (roughness, fine lines, radiance, firmness, elasticity) were noted. In comparison to week 0, the following mean percent improvements in skin parameters were noted at week 12: roughly 23% improvement in fine lines, almost 20% in roughness, 15% in both radiance and firmness, and roughly 13% in elasticity. Clinical grading for roughness, lack of clarity, global fine lines, lack of radiance/brightness, and elasticity also showed statistically significant improvement at all weeks (1, 4, 8, 12). Otherwise, under-eye wrinkles, crow’s feet wrinkles, look of skin firmness/laxity, feel or skin firmness/laxity, lack of skin elasticity, and overall unevenness of skin tone also all reached statistically significant clinical improvement by week 4 and beyond. Other statistically significant reductions included photoaging and visual improvement in signs of aging (weeks 8+12), and skin glycation index (week 12).

Subjective data also reinforced the efficacy of the AP31 formulation, with 70% of patients reporting improved radiance, tone and texture as early as week 1, with the number rising to 93% at 12 weeks in at least 3 clinical signs of early collagen decline. Additionally, 87% noted a statistically significant improvement in elasticity and skin firmness, while the subjects agreed that they felt that their skin had a healthy glow with a more luminous appearance. Importantly, roughly 70% of patients reported that they could consider delaying neuromodulatory injectable therapies after using the AP31 formulation. Finally, dynamic expression lines, caused by repeated mechanical stress secondary to facial expression and resulting in dynamic and eventually permanent wrinkles, were evaluated by dynamic facial imaging techniques. The lines were noted to have faster recovery after 12 weeks of AP31 formulation application, decreasing their long-term impact on the skin.

Tolerability

The product regimen was well-tolerated overall, with early and sustained statistically significant improvements in dryness/scaling and tightness/dry feeling. There were no increases in irritation signs or symptoms. Two adverse effects with a possible relationship to the test product or study procedures were noted, with a report of a unilateral eye infection and another of a skin-burning sensation on the face.

Other Available Treatment Modalities Currently Available for Pre-Aging

Currently, therapies available for the management of pre-aging can be divided into four categories, namely topical products, minimally invasive procedures, lifestyle changes and emerging therapies.

Topical products, including retinol, vitamin C, niacinamide, peptides and sunscreens, assist in protecting and preserving pre-aging skin by correcting early signs of aging. Retinoids (retinol, retinaldehyde, tretinoin) work by stimulating collagen synthesis and cell turnover, thereby improving skin tone and texture and reducing early fine lines.^{10, 11} Antioxidants (vitamin C or E, ferulic acid, resveratrol) neutralize free radicals and reduce oxidative stress, preventing pigmentation and dullness and boosting collagen production (especially vitamin C).^12-14 Peptides (AP31, matrixyl, argireline) support extracellular matrix health and skin firmness, and may reduce inflammation or mimic neuromodulators.^{15, 16} Bakuchiol, a retinol alternative, is less irritating, and can be offered to patients with retinol sensitivity, and overall skin sensitivity, with anti-oxidant, anti-inflammatory and anti-acne effects.¹ Notably, AP31 in combination with bakuchiol as a commercially available formulation (Neutrogena Collagen Bank Moisturizer^®) intends to deliver synergistic benefit. Finally, broad spectrum SPF 30-50 sunscreen is undeniably the most important anti-aging product at any stage, preventing UV-induced collagen breakdown and pigmentation.^{17, 18}

Minimally invasive procedures, such as chemical peels, microneedling, neuromodulators and energy-based devices, help by stimulating collagen, refining texture, and preventing lines. Chemical peels exfoliate the epidermis to encourage cell renewal and to brighten dull skin.^{19, 20} Microneedling produces controlled skin injury, thereby inducing collagen production and improving texture, acne scars and early wrinkles.^{21, 22} Intense pulsed light therapy targets redness, pigmentation and dullness,^{23, 24} while low-energy fractional lasers boost collagen.²⁵ Low-dose botulinum toxin is commonly used for wrinkle reduction, especially in highly affected facial zones such as the forehead, glabella and upper lip, and works by decelerating habitual expression lines from becoming permanent.²⁶

Modifiable lifestyle factors can decrease signs of pre-aging by reducing intrinsic aging triggers. Skin health can be supported through proper nutrition, ensuring a diet rich in antioxidants such as vitamin C, carotenoids, polyphenols, while collagen peptides and omega-3s may reduce inflammation and support the extracellular matrix.^{27, 28} Sleep and stress should be optimized, given that poor sleep and high cortisol result in oxidative stress and glycation, accelerating aging.^{29, 30} Glycation of collagen and elastin reduces their viscoelastic properties, resulting in histologic findings of stiffness and rigidity and clinical observations of sagging and loss of elasticity.^31-34 Conversely, good quality sleep promotes skin repair and hydration balance, improving skin appearance. Smoking and alcohol should be avoided, as smoking depletes skin oxygen and destroys collagen, while alcohol causes dehydration and oxidative stress.^{35, 36}

Lastly, emerging therapies include exosome-based serums, topical growth factors (EGF, TGF-β), blue or red light therapy, and topical nicotinamide adenine dinucleotide (NAD) boosters (e.g. niacinamide, NMN), which target cellular health and repair mechanisms. Exosome-based serums are hypothesized to stimulate repair and reduce inflammation, while topical growth factors promote healing and extracellular matrix remodelling.^{37, 38} Low levels of blue or red light therapy reduces inflammation and increases intracellular energy.^39-41 Topical NAD boosters support cellular energy and repair, enhancing cellular energy metabolism, DNA repair and skin barrier function.^{42, 43}

Conclusion

Acetyl dipeptide-31 amide is a novel micropeptide that has been shown to be an efficacious treatment modality to improve the appearance of pre-aging. Its anti-aging capacities are due to its anti-inflammatory effects, extracellular matrix support and favorable influence on skin aging-related cellular pathways and genes involved in barrier function, skin hydration, skin plumping and epidermal metabolism. Overall, the data supports that such an early intervention is beneficial to protect and preserve youthful skin. Given favourable molecular and clinical observations in clinical studies using formulations containing AP31, there is a role for use of the ingredient in both the young and mature, for preaging and anti-aging benefits respectively. Considering its efficacy, safety and tolerability profiles, AP31 should be contemplated first-line when young adults seek pre-aging interventions. Further studies would be valuable to compare the effectiveness of AP31 relative to, and in combination with established pre-aging modalities, as well as longitudinal evaluation to determine its skin impact over time.